Topical or transdermal delivery systems for the administration of drugs are known to offer several advantages over oral delivery of the same drugs. Generally, the advantages of topical or transdermal delivery of drugs relate to pharmacokinetics. More specifically, one common problem associated with the oral delivery of drugs is the occurrence of peaks in serum levels of the drug, which is followed by a drop in serum levels of the drug due to its elimination and possible metabolism. Thus, the serum level concentrations of orally administered drugs have peaks and valleys after ingestion. These highs and lows in serum level concentrations of drug often lead to undesirable side effects.
In contrast, topical and transdermal delivery of drugs provides a relatively slow and steady delivery of the drug. Accordingly, unlike orally administered drugs, the serum concentrations of topically or transdermally delivered drugs are substantially sustained and do not have the peaks associated with oral delivery.
The sustained serum concentrations associated with topical or transdermal drug delivery avoids the systemic side effects of oral administration of drugs. Specifically, first pass metabolism of the drug by the liver is circumvented by utilizing transdermal or topical delivery vehicles for the administration of drugs.
For example, there is a significant decrease in adverse effects associated with the transdermal delivery of oxybutynin. Oxybutynin is an antispasmodic, anticholinergic agent. Oxybutynin is administered as a racemate of R- and S-isomers. Chemically, oxybutynin is d,l (racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate. The empirical formula of oxybutynin is C22H31NO3, Oxybutynin has been found to have a direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle, but exhibits only one-fifth of the anticholinergic activity of atropine detrusor muscle (effect observed in rabbits), and four to ten times its antispasmodic activity. Oxybutynin has not been found to possess blocking effects at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects). Moreover, oxybutynin has been found to relax bladder smooth muscle.
In patients with conditions characterized by involuntary bladder contractions, cystometric studies have demonstrated that oxybutynin increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void. Oxybutynin thus decreases urgency and the frequency of both incontinent episodes and voluntary urination. It has also been reported that antimuscarinic activity resides predominantly in the R-isomer. Oral oxybutynin is widely used or the relief of symptoms of bladder instability associated with voiding in patients with uninhibited neurogenic or reflex neurogenic bladder, i.e., urgency, frequency, urinary leakage, urge incontinence, and dysuria.
Until recently oral anticholinergic medications have been the primary pharmacotherapy for the treatment of urge urinary incontinence and overactive bladder (OAB), among which oxybutynin is the golden standard medication. There are several different drug products available on the international market for oral administration of oxybutynin, including immediate- and extended-release formulations. Both have been shown to be effective in the treatment of OAB. However, their compliance has been limited by anticholinergic side effects. Adverse reactions associated with oxybutynin therapy, however, may include cardiovascular manifestations such as palpitations, tachycardia or vasodilatation; dermatologic manifestations such as decreased sweating, rash; gastrointestinal and genitourinary manifestations such as constipation, decreased gastrointestinal motility, dry mouth, nausea, urinary hesitance and retention; nervous system manifestations such as asthenia, dizziness, drowsiness, hallucinations, insomnia, restlessness; opthalmic manifestations such as amblyopia, cycloplegia, decreased lacrimation, mydriasis. Most common side effects associated with oral oxybutynin encompasses dry mouth, dizziness, blurred vision, and constipation. These adverse experiences may be uncomfortable enough to substantially limits long-term patient compliance (<18% at 6 months). Oral formulations of oxybutynin indeed undergo hepatic metabolism to form N-desethyloxybutynin (DEO), which is considered to be the primary underlying cause of dry mouth associated with anticholinergic therapy. See Appell R. A., Chancellor M. B., Zobrist R. H., Thomas H., Sanders S. W., “Pharmacokinetics, metabolism, and saliva output during transdermal and extended-release oral oxybutynin administration in healthy subjects”, Mayo Clin Proc. 78: 696-702; 2003, the entire content of which is herein incorporated as reference. See also Kelleher C. J., Cardozo L. D., Khullar V., Salvatore S., “A medium-term analysis of the subjective efficacy of treatment for women with detrusor instability and low bladder compliance.”, Br J Obstet Gynaecol. 104: 988-93; 1.997, the entire content of which is herein incorporated as reference.
The development of an extended-release formulation of oxybutynin was intended to preserve the efficacy of the drug while reducing the incidence and severity of dry mouth and other anticholinergic side effects. Extended-release formulations allow once-a-day dosing and provide a more consistent therapeutic drug level in the blood throughout the day and less metabolite generation. This lower DEO metabolite generation is associated with reduced adverse effects. Recently, a transdermal patch of oxybutynin (OXYTROL®, Watson Pharmaceuticals, Inc.) has entered the marketplace as a therapeutic option for OAB. Transdermal administration of oxybutynin leads to clinically important changes in the pharmacokinetics, metabolism, and pharmacodynamic effects of oxybutynin compared with extended-release oral treatment. Transdermal administration of oxybutynin, as any other route of administration avoiding gastrointestinal and hepatic first-pass metabolism, results in lower fluctuation in oxybutynin plasmatic levels, in reduced DEO metabolite formation, and in increased saliva production. Lower DEO plasma concentrations and greater saliva output are thought to correspond to the reported low incidence of dry mouth in patients treated with transdermal oxybutynin. See, Dmochowski R R, Davila G W, Zinner N R, Gittelman M C, Saltzstein D R, Lyttle S, Sanders S W; For The Transdermal Oxybutynin Study Group.; “Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence”, The Journal of Urology, Vol. 168, 580-586, August 2002, the entire content of which is herein incorporated as reference. Phase III studies comparing OXYTROL® patch to oral extended-release tablet (DITROPAN® XL, Ortho McNeil Janssen) showed that only 4.1% of the patients on transdermal therapy reported dry mouth, whereas 60.8% of the patients on oral treatment reported this side effect. This reduction of incidence of dry mouth, together with the improvement of overactive bladder symptoms, is responsible for a better quality of life seen in patients treated with transdermal oxybutynin compared to oral oxybutynin therapy. Thus, it can be easily seen that transdermal delivery of oxybutynin has been shown to be more advantageous, as well as preferred over oral delivery of oxybutynin.
Oxybutynin has also been suggested as a possible treatment for hyperhidrosis. Sweating is a physiological response to heat which affords protective evaporative cooling through the skin. Sweating in excess of what is required for thermoregulation by exocrine sweat glands is called hyperhidrosis. The sweat glands are innervated by the sympathetic nervous system. The released peripheral transmitter, acetylcholine, binds to localized muscarinic receptors on the sweat glands and trigger sweat production. When the body's internal temperature exceeds the hypothalamic set point, activation of a sympathetic reflex causes an increase in sweat output. Evaporation of the sweat then leads to a decrease in body temperature. These glands, while present over the entire body surface, are most concentrated on axillae (armpits), face, palms, and soles followed by back and chest.
Hyperhidrosis refers to the overproduction of sweat by sweat glands. Primary focal hyperhidrosis is the more frequent condition and is often idiopathic. It is generally localized to the face, hands, feet, axillae or a combination of these. Secondary hyperhidrosis is linked to dysfunction of the peripheral or central nervous system and can be secondary to other diseases, metabolic disorders, febrile illnesses, and drugs (i.e., an iatrogenic event or complication). Hyperhidrosis affects about 1% of the population and includes people of both sexes and all races.
While generally considered non-life-threatening, hyperhidrosis can cause emotional distress and social embarrassment as well as destruction of private and professional lives. Additionally, hyperhidrosis can aggravate skin disorders like dermatitis and eczema and can result in loss of excess fluids from the body and electrolytes from the body.
Current treatments for hyperhidrosis are symptomatic unless a physiological cause is identified. In patients with primary hyperhidrosis or for symptomatic treatment of heavy sweating in patients with secondary hyperhidrosis, not treatable otherwise, treatments include local injections of botulinum toxin, surgical removal of sweat glands, topical deodorants containing aluminum, treatment with electric currents and systemic use of anti-cholinergic drugs. Unfortunately, botulinum toxin treatments are expensive and, due to its nature, surgery is generally performed only as a last resort.
Anti-cholinergic drugs have been mentioned as being effective at reducing sweating but the dosages required to achieve reduced sweating also result in adverse side effects including dryness of the mouth, constipation, blurred vision, decreased sexual ability, lack of appetite, nausea, somnolence, feeling of raised temperature and more. Most patients with localized or generalized hyperhidrosis can not tolerate them for extended periods. One way to counter this is to administer such drugs topically through iontophoresis—a variation on the water iontophoresis treatment. Alternatively, the use of the drug would be occasional so as to minimize contact.
Other uses of anti-cholinergic agents have been described. U.S. Pat. No. 5,258,388 discloses anti-cholinergic/anti-secretory agents useful as mydriatics and as antiperspirants. US Patent Application Publication No. 20040192754 provides methods for treating idiopathic hyperhidrosis comprising administering to a patient compounds which reduce the activity of a 5-HT2C receptor alone or concurrently with antiperspirants, tranquilizers and anti-cholinergic agents, such as oxybutynin.
Until recently, the primary dosage form for oxybutynin is oral medications. Most common side effects associated with oral oxybutynin encompasses dry mouth, dizziness, blurred vision, constipation and dermatologic manifestations such as decreased sweating. These adverse experiences may be uncomfortable enough to substantially limits long-term patient compliance (<18% at 6 months). Oral formulations of oxybutynin undergo hepatic metabolism to form N-desethyloxybutynin (DEO), which is considered to be the primary underlying cause of dry mouth associated with anti-cholinergic therapy.
Oral oxybutynin was shown to be useful in treating the relatively rare syndrome of episodic hyperhidrosis with hypothermia (LeWitt, 1988). More recent reports also shows that oral administering oxybutynin treats hyperhidrosis, See Mijnhout et al. Oxybutynin: dry days for patients with hyperhidrosis, Neth J. Med. 2006 October; 64(9):326-8; Tupker et al., Oxybutynin therapy for generalized hyperhidrosis, Arch Dermatol. 2006 August; 142(8):1065-6; Kim et al., Acta Derm Venereol. 2010 May; 90(3):291-3; Wolosker et al., The use of oxybutynin for treating axillary hyperhidrosis, Ann Vasc Surg. 2011 November; 25(8):1057-62. US 2008/0207737 discloses the topical application of a composition comprising a therapeutically effective amount of anti-cholinergic agents, such as oxybutynin for treating hyperhidrosis.
Although the transdermal and/or transmucosal delivery of oxybutynin overcome some of the problems associated with oral administration of oxybutynin, such as that described above, this route of administration is not free of its own drawbacks. Transdermal patches very often cause allergic reactions and skin irritations due to their occlusive nature, or due to their composition (incompatibility reactions with the polymers used). In the OXYTROL® phase III study, 16.8% of the patients reported itching at the patch application site as an adverse effect. A transdermal oxybutynin gel should combine the advantages of the transdermal route (reduced side effects related avoidance of first-pass metabolism leading to lowered formation of DEO metabolite; steady plasmatic levels) with a low potential for skin irritation. Since an oxybutynin gel would be applied directly to the skin, skin reactions associated with the adhesive properties and the occlusive nature of transdermal patch formulations (e.g. OXYTROL®) should be avoided.
Besides skin irritation and tolerance considerations, an issue of transdermal drug delivery systems is that these systems are typically restricted to low-molecular weight drugs and those with structures having the proper lipophilic/hydrophilic balance. High molecular weight drugs, or drugs with too high or too low hydrophilic balance, often cannot be incorporated into current transdermal systems in concentrations high enough to overcome their impermeability through the stratum corneum. Efforts have been made in the art to chemically modify the barrier properties of skin to permit the penetration of certain agents (since diffusion is primarily controlled through the stratum corneum), enhance the effectiveness of the agent being delivered, enhance delivery times, reduce the dosages delivered, reduce the side effects from various delivery methods, reduce patient reactions, and so forth. In this regard, penetration enhancers have been used to increase the permeability of the dermal surface to drugs.
Various permeation enhancers have been reported as being effective for the transdermal or topical delivery of oxybutynin. For example, U.S. Pat. Nos. 5,411,740, 5,500,222, and 5,614,211, each discloses monoglyceride or a mixture of monoglycerides of fatty acids as the preferred permeation enhancer for an oxybutynin transdermal therapeutic system. U.S. Pat. No. 5,736,577 describes a pharmaceutical unit dosage form in for transdermal administration of (S)-oxybutynin comprising a permeation enhancer. U.S. Pat. No. 5,747,065 discloses monoglycerides and esters of lactic acid as a permeation enhancing mixture for oxybutynin. U.S. Pat. Nos. 5,834,010 and 6,555,129 both disclose triacetin as a permeation enhancer for oxybutynin. U.S. Pat. No. 5,843,468 describes a dual permeation enhancer mixture of lauryl acetate and a glycerol monolaurate for transdermal administration of oxybutynin. U.S. Pat. No. 6,004,578 disclose permeation enhancers selected from the group consisting of alkyl or aryl carboxylic acid esters of polyethyleneglycol monoalkyl ether, and polyethyleneglycol alkyl carboxymethyl ethers for a transdermal matrix drug delivery device comprising oxybutynin. Meanwhile, U.S. Pat. No. 6,267,984 discloses skin permeation enhancer compositions comprising a monoglyceride and ethyl palmitate for transdermal delivery of oxybutynin. U.S. Pat. No. 6,562,368 discloses the use of hydroxide-releasing agent to increase the permeability of skin or mucosal tissue to transdermally administered oxybutynin. U.S. Pat. Nos. 7,029,694 and 7,179,483 relate to oxybutynin gel formulations that include permeation enhancers as optional components, among which triacetin and monoglycerides are preferred permeation enhancers. International Patent Application Publication No. WO 2005/107812 discloses a transdermal composition comprising a urea-containing compound in a carrier system for enhanced systemic delivery of an anti-cholinergic agent.
The most common penetration enhancers, however, are toxic, irritating, oily, odiferous, or allergenic. Specifically, the penetration enhancers used and thought to be necessary to transdermally deliver oxybutynin, namely, long-chain acids such as lauric acid and oleic acid, long-chain alcohols such as lauryl or myristyl alcohol, and long-chain esters such as triacetin (the glycerol trimester of acetic acid), glycerol monolaurate or glycerol monooleate, tend to include aliphatic groups that make the formulations oily and malodorous.
Thus, there is a need in the industry for a transdermal formulation that is noninvasive, easy to administer and minimizes side effects while adequately delivering oxybutynin to patients with skin tolerability, but which does not include the unpleasant odor common to the prior art formulations. The present invention now satisfies that need.